Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine discovered decades ago. TNF-α is produced by diverse types of cells in response to inflammatory and immunological stimuli. [Trends Cell. Biol. vol 5, 392-399 (1995)] For example, monocytes treated with lipopolysaccharide (LPS) significantly increases the production of TNF-α. Although TNF-α was also known to shrink tumors through apoptosis, it plays a central role in inflammation and immunology.
Abundant presence of TNF-α has been observed in a variety of immunological disorders including but not limited to rheumatoid arthritis, psoriasis, eczema, Crohn's disease, chronic obstructive pulmonary disease (COPD), systemic lupus erythematosus (SLE), sepsis, endotoxin shock, multiple sclerosis, chronic hepatitis, and so on. [J. Med. Chem. vol 42, 2295-2314 (1999); Am. J. Respir. Crit. Care Med. vol 153, 633-637 (1996); Lupus vol 11, 102-108 (2002); Hepatogastroenterology. vol 47, 1675-1679 (2000)]
Blockade or neutralization of the TNF-α activity by a TNF-α monoclonal antibody has been found effective in treating immunological disorders including but not limited to rheumatoid arthritis, ankylosing spondylitis, Crohn's disease and psoriatic arthritis, as seen with the cases of infliximab (Remicade™) and adalimumab (Humira™). [Remicade™ (infliximab) Prescribing Information. Centocor Inc. September 2005; Humira™ (adalimumab) Prescribing Information. Abbott Lab October 2005.] Etanercept (Enbrel™) is a fusion protein with the decoy receptor part for TNF-α and therefore neutralizes the biological activity of TNF-α. Etanercept is indicated for rheumatoid arthritis, ankylosing spondylitis, psoriasis, and psoriatic arthritis in the US. [Enbrel™ (etanercept) Prescribing Information. Immunex Corporation. July 2005.] These protein drugs are currently available by injectable formulations only.
To date many biological targets are known to inhibit the cellular production of TNF-α. Pro-TNF-α is cleaved into the active soluble form of TNF-α by TNF-α converting enzyme (TACE). [Nature vol 385, 729-733 (1997)] Production of TNF-α is decreased by an increase in the cytosolic level of cAMP. Since inhibition of phosphodiesterase 4 (PDE4) increases the cytosolic level of cAMP, PDE4 inhibitors, such as rolipram, cilomilast and roflumilast, attenuate the production of TNF-α. [Curr. Pharm. Design vol 8, 1255-1296 (2002)] Adenosine receptor A2a is coupled with adenylate cyclase and its agonists, such as CGS21680 and NECA, inhibit the synthesis of TNF-α. [Drug Devel. Res. vol 45, 103-112 (1998)] Kinases such as NIK, IKK, and PKB, which are involved in the signaling of NF-κB, are known to suppress the production of TNF-α if inhibited. IKK inhibitors such as BMS-345541 block phosphorylation on IκB and inhibit the NFκB-dependent transcription. [J. Biol. Chem. vol 278, 1450-1456 (2003)] 5-aminosalicylic acid is known to inhibit IKK at therapeutically relevant dose for inflammatory bowel disease (IBD). Aspirin, a traditional nonsteroidal anti-inflammatory drug, is also known to inhibit IKK at high dose level. [Nature vol 396, 77-80 (1998)] Inhibition of MAP kinases such as p38 and c-Jun N-terminal kinase (JNK) suppresses the TNF-α production. p38 inhibitors such as VX-745 and SB203580 inhibited TNF-α production in cells treated with LPS, and showed therapeutic effect in animal models for rheumatoid arthritis. [Curr. Opin. Investig. Drugs vol 5, 566-571 (2003)] Thalidomide is indicated for systemic lupus erythematosus (SLE), although thalidomide weakly inhibits the synthesis of TNF-α at cellular level. It appears that thalidomide destabilizes TNF-α mRNA to decrease the TNF-α production. [Clin. Exp. Immunol. vol 110, 151-154 (1997)] Steroids also potently inhibit production of TNF-α. [J. Exp. Med. vol 172, 391-394 (1990)]
Reflecting that TNF-α plays a central role in inflammation and immunology, agents inhibiting the biological activity or production of TNF-α are expected to show therapeutic effect in a variety of disorders such as rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, inflammatory bowel disease including ulcerative colitis and Crohn's disease, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus (SLE), chronic obstructive pulmonary disease (COPD), sepsis, endotoxin shock, hepatitis, Type I diabetes, and so on. Some types of agents were found more effective for some disorders than others, depending on the mode of action and their physiochemical properties. PDE4 inhibitors such as roflumilast and cilomilast, for example, have been heavily developed for COPD. On the other hand, anti-TNF-α biologics were initially indicated for rheumatoid arthritis, and their indications are expanding to include ankylosing spondylitis, psoriasis, and Crohn's disease. 5-aminosalicylic acid and sulfasalazine are used to treat moderate to mild inflammatory bowel disease, while steroids and anti-TNF-α biologics are indicated for severe cases. There have been attempts to treat inflammatory bowel disease using PDE4 inhibitors. [Ann. Rev. Med. Chem. vol 38, 141-152 (2003)] Although p38 inhibitors such as VX-702 were evaluated for human rheumatoid arthritis, their therapeutic utility remains to be established for MAP Kinase inhibitors. [Curr. Opin. Drug Discov. Devel. vol 8, 421-430 (2005)] Steroids are initially effective for diverse kinds of immunological disorders, however, their long term use is strongly limited due to adverse events.
Although anti-TNF-α biologics such as infliximab, adalimumab and etanercept are widely used to treat immunological disorders such as rheumatoid arthritis and psoriasis, these protein drugs are doomed to be expensive and administered by injection. In this regard, small molecules inhibiting the action or production of TNF-α are in strong demand due to cost and convenience of avoiding injection.